| Structural highlights
7js8 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.634Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
HDAC2_HUMAN Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.[1]
Publication Abstract from PubMed
We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.
Discovery of Ethyl Ketone-Based Highly Selective HDACs 1, 2, 3 Inhibitors for HIV Latency Reactivation with Minimum Cellular Potency Serum Shift and Reduced hERG Activity.,Yu W, Liu J, Clausen D, Yu Y, Duffy JL, Wang M, Xu S, Deng L, Suzuki T, Chung CC, Myers RW, Klein DJ, Fells JI, Holloway MK, Wu J, Wu G, Howell BJ, Barnard RJO, Kozlowski J J Med Chem. 2021 Apr 22;64(8):4709-4729. doi: 10.1021/acs.jmedchem.0c02150. Epub , 2021 Apr 2. PMID:33797924[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kajiwara Y, Akram A, Katsel P, Haroutunian V, Schmeidler J, Beecham G, Haines JL, Pericak-Vance MA, Buxbaum JD. FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. PLoS One. 2009;4(4):e5071. doi: 10.1371/journal.pone.0005071. Epub 2009 Apr 3. PMID:19343227 doi:10.1371/journal.pone.0005071
- ↑ Yu W, Liu J, Clausen D, Yu Y, Duffy JL, Wang M, Xu S, Deng L, Suzuki T, Chung CC, Myers RW, Klein DJ, Fells JI, Holloway MK, Wu J, Wu G, Howell BJ, Barnard RJO, Kozlowski J. Discovery of Ethyl Ketone-Based Highly Selective HDACs 1, 2, 3 Inhibitors for HIV Latency Reactivation with Minimum Cellular Potency Serum Shift and Reduced hERG Activity. J Med Chem. 2021 Apr 22;64(8):4709-4729. PMID:33797924 doi:10.1021/acs.jmedchem.0c02150
|
